Polynucleotide delivery to cardiac tissue

a polynucleotide and tissue technology, applied in the field of cardiology, can solve the problems of drug degradation, drug degradation, and difficulty in delivering therapeutically active agents to cardiac tissue, and achieve the effect of improving or maintaining the ejection fraction of the cardiovascular system and improving the ejection fraction

Inactive Publication Date: 2006-07-06
OSPREY MEDICAL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0037] A further aspect of any of the embodiments of the invention including a viral vector, comprises the addition of less than about 1×1013, 1×1012, 1×1011, 1×1010, 1×109, or 1×108 viral particles to the fluid in the artificial flow path; and/or that the viral vector transfects at least equal to, or about, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or 100% of cardiomyocytes of the targeted vascular territory. The number of viral vector can also be a therapeutically effective amount, such that a sufficient amount of polynucleotide is delivered to the cardiac tissue to effect a therapeutic result.
[0038] Another aspect of any of the embodiments of th...

Problems solved by technology

Coronary artery disease and heart failure are possibly the most serious and prevalent, together being a leading cause of death in the Western world.
While there is continual discovery of new and efficacious compounds to treat heart disease, delivery of the therapeutically active agents to cardiac tissue can be problematic.
For example, the structure of many pharmaceuticals may be altered by the liver, destroying their therapeutic activity.
However, after these routes of administration the drug can still be degraded on subsequent passes through the liver.
Another problem relates to toxicity of therapeutic agents.
For example, a drug administered to target a tumor of the heart may have a toxic effect on healthy tissue in...

Method used

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  • Polynucleotide delivery to cardiac tissue
  • Polynucleotide delivery to cardiac tissue
  • Polynucleotide delivery to cardiac tissue

Examples

Experimental program
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Effect test

example 1

Recirculating Delivery of a Pseudophosphorylated Mutant of Phospholamban (S16E) Prevents the Progression of Heart Failure in a Large Animal Model

[0197] Using an embodiment of a cardiac isolation circuit described herein, the coronary venous circulation in a sheep was isolated from the systemic circulation. This isolated cardiac circuit provided a recirculating percutaneous system for the selective delivery of viral vectors to myocardium. Using this system, adenovirus (3.5×1012vp) encoding a pseudophosphorylated mutant of phospholamban was delivered to sheep as described below. The sequence of wild-type human phospholamban (PLN) is obtainable from Genbank under accession number NM—002667, incorporated herein by reference. The pseudophosphorylated mutant used in this study (S16E) is a point mutation of phospholamban at amino acid 16 from S to E.

[0198] Animal Procedures

[0199] Day 0—Cardiac Pacemaker Implantation

[0200] Anesthesia and Site Preparation

[0201] The animal foreleg was cl...

example 2

Delivery of SERCA2a to Cardiac Cell

[0227] Using a the same technique as in Example 1 for isolating the coronary venous circulation and delivering viral vector to sheep myocardium, adenovirus was delivered (3.5×1012vp) encoding the sarcoplasmic reticulum ATPase 2a (AdSERCA2a (n=2)) or adenovirus encoding a control gene for β-Galactosidase (LacZ;AdLacZ (n=6, 4.7×1012vp) to sheep with pacing induced heart failure. The sequence of human SERCA2a can be obtained at Genbank accession numbers NM—170665 and NM—001681, incorporated herein by reference. Despite 2 weeks further pacing, treatment with AdSERCA2a significantly improved contractile function despite ongoing pacing stress and prevented ventricular remodeling in contrast to AdLacZ animals, as shown in FIG. 5.

example 3

Delivery of β-Galactosidase to a Cardiac Cell

[0228] Using the same technique as in Example 1 for isolating the coronary venous circulation and delivering viral vector to sheep myocardium described in Examples 1 and 2, we delivered adeno-associated virus (2×1012vp) encoding the gene for β-Galactosidase (LacZ ) [AAV2 / LacZ]. Immunohistochemical staining for β-Galactosidase in heart indicated high efficiency transduction of the majority of cardiomyocytes in treated vs. control, non-treated animals (see FIG. 6). The Ad / LacZ was made as described in Hoshijima, M., et al. Nat. Med. 8:864-871 (2002).

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Abstract

A method for delivering a polynucleotide to cardiac tissue, including substantially isolating the coronary venous circulation from systemic circulation, and introducing a polynucleotide into the isolated coronary venous circulation to effect localized transfection of cardiac tissue. The polynucleotide advantageously produces a therapeutic effect, such as increasing or decreasing the expression level of a protein in the cardiac tissue.

Description

[0001] This application is a continuation-in-part of PCT / AU2005 / 000237, filed month / day / year, which is hereby incorporated by reference in its entirety.FIELD OF THE INVENTION [0002] The present invention relates to the field of cardiology and more specifically to the delivery of therapeutic polynucleotides to cardiac tissue. BACKGROUND TO THE INVENTION [0003] Heart disease is a major public health issue of very high prevalence, especially in the Western world. Cardiac conditions include coronary artery disease, ischaemic heart disease, heart failure, valvular heart disease, cardiac arrhythmias and cardiac inflammation (myocarditis) to name a few. Coronary artery disease and heart failure are possibly the most serious and prevalent, together being a leading cause of death in the Western world. The impact of acute myocardial infarction and congestive heart failure and their sequelae on the quality of life of patients and the cost of health care drives the search for new therapies. [00...

Claims

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Application Information

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IPC IPC(8): A61K48/00A61M25/00
CPCA61B2017/00252A61M1/3653A61M25/1002A61M25/1011A61M2025/1047A61M2025/1052A61M2210/127C12N9/14C12N2799/022C12N2799/025
Inventor KAYE, DAVID MARTINPOWER, JOHN MELMOUTHALFERNESS, CLIFTON A.BILNEY, ADAM LUCASCHIEN, KENNETHPREOVOLOS, ATHANASIOS CRISTOS
Owner OSPREY MEDICAL
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